title: Residual CD95-pathway function in children with autoimmune lymphoproliferative syndrome is independent from clinical state and genotype of CD95 mutation.
abstract: Human autoimmune lymphoproliferative syndrome (ALPS) is caused by defective CD95-mediated apoptosis of lymphocytes. In most patients, heterozygous mutations within the CD95 gene are found. Mutated proteins interfere with CD95-signaling in a dominant-negative way. However, the penetrance of clinical disease is variable. We describe 13 patients out of nine families with the clinical presentation of ALPS. Eight different mutations were detected. Sensitivity to CD95-induced cell-death, assembly of the CD95-death-inducing signaling complex (DISC), and activity of initiator caspases-8 and -10 were compared in EBV-transformed B-lymphoblastoid cells of these patients. All CD95-mutations led to a reduced DISC formation and diminished initiator caspase activity upon CD95-stimulation, whereas a marked heterogeneity in sensitivity to CD95-induced killing was found. Residual apoptosis sensitivity to almost normal levels could be achieved upon cross-linking by addition of protein A. Thus, no correlation between residual CD95 sensitivity and clinical phenotype or genotype of ALPS was found. This observation is only partially explained by the variable effects of the CD95-mutations themselves. It also points to a pronounced influence of additional factors, such as modifier pathways or exogenous effects apart from the CD95 pathway in the pathogenesis of ALPS.
authors.affiliation: Children's Hospital, University of Ulm, Ulm 89073, Germany. klaus-michael.debatin@uniklinik-ulm.de
authors.forename: Hans
authors.initials: H
authors.lastname: Fuchs
authors.forename: Carsten
authors.initials: C
authors.lastname: Posovszky
authors.forename: Georgia
authors.initials: G
authors.lastname: Lahr
authors.forename: Jutte
authors.initials: J
authors.lastname: van der Werff ten Bosch
authors.forename: Thomas
authors.initials: T
authors.lastname: Boehler
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D053455:Caspase 10 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000276:immunology; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D005838:Genotype; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D013205:Staphylococcal Protein A / Q000378:metabolism; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C491901:FAS protein, human; D013205:Staphylococcal Protein A; D019014:fas Receptor; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human